RU2667468C2 - Method for treating damage of musculoskeletal system related to solution of continuity, pharmaceutical medication for its implementation and use of chondroitin sulfate for accelerating formation of fibrocartilagenous callus - Google Patents

Abstract

FIELD: medicine.SUBSTANCE: group of inventions relates to medicine and relates to a method for treating musculoskeletal injuries associated with solution of continuity by stimulating the formation of a bone callus comprising injecting chondroitin sulfate intramuscularly. Chondroitin sulfate is administered at a dose of 100 to 200 mg every other day, a total course of 10–14 injections, wherein the 1st injection of chondroitin sulfate is given to a patient as soon as possible after the injury, mainly on the day of the injury or the next day. Wherein the 1st injection of chondroitin sulfate is administered at 100 mg, and starting with the 3rd, or 4th, or 5th, or 6th injections of chondroitin sulfate, 200 mg are administered. Also, the group of inventions relates the use of chondroitin sulfate in an amount of 10–14 injections of 100–200 mg to accelerate the formation of bone callus in the treatment of musculoskeletal injuries associated with solution of continuity.EFFECT: group of inventions provides an increase in the frequency of formation of bone callus and an increase in the rate of formation of bone callus due to the acceleration of the formation of fibrous cartilaginous calluses and their mineralization.3 cl, 6 dwg, 15 tbl, 1 ex

Description

The invention relates to medicine, namely to traumatology, and for the treatment of injuries of the musculoskeletal system associated with a violation of the integrity of the bone (cracks and fractures), including with closed fractures of the radius, and can be used for faster formation of bone marrow with fractures and cracks.

Fusion of bones during cracks or fractures is a natural biological process, which in the vast majority of cases should lead to the restoration of its integrity and the resumption of physiological functions. In tissue regeneration after injury, the main role belongs to the biological process fixed in evolution, which occurs automatically, stereotypically, and stage by stage leads to the final phenomenon - regeneration. However, many factors can affect this process: gender, age, individual characteristics of the body, the presence of concomitant diseases, such as diabetes mellitus, which significantly reduce the time of fusion of injured tissue.

Especially important is the fact that trauma is also experienced by young people who have a long-term decline in working capacity, and elderly patients who, as a result of pathological processes, disrupt the bone tissue repair process. Therefore, it is obvious that the problem of reducing the terms of fracture fusion is not only a medical, but also a socio-economic problem.

An active search is currently underway for new agents that stimulate bone regeneration. Therefore, it was proposed to study the effect of the drug chondroitin sulfate on the regenerative processes of bone tissue.

In the treatment of bone fractures, in addition to standard basic therapy (fixation of the bone by applying a plaster cast and prescribing analgesics), “concomitant therapy” is also used.

So it is known additional intramuscular administration of vitamins in the treatment of bone fractures in parallel with standard basic therapy. (USSR AS No. 1268169 A method for treating bone fractures. Application: 4802826. Filing date: 12/07/1989. Published: 01/23/1993). The introduction of vitamins increases the body's defenses, but does not directly affect bone regeneration.

A lyophilized pharmaceutical composition is known which contains chondroitin sulfate based on the addition of sodium bisulfite as a stabilizer. (RF patent No. 2458693 Lyophilized pharmaceutical composition for the preparation of an injection for the treatment of degenerative diseases of the musculoskeletal system and the method for its preparation. Application: 2011131516/15. Date of filing: 07/28/2011. Published: 08/20/2012). The main areas of application of this composition are degenerative diseases of the joints and spine: primary arthrosis, intervertebral osteochondrosis, osteoarthritis, osteoporosis, periodontopathy, bone fractures (to accelerate the formation of bone marrow).

However, the specified source does not provide methods for using the claimed composition for fractures. There are no data on the necessary dosages and timing of treatment.

Closest to the proposed invention is a method of treating fractures comprising additional intramuscular administration of chondroitin sulfate. (RF patent No. 2416411 A method for treating fractures of long tubular bones. Application: 2008150987/14. Date of filing: 12/22/2008. Date of publication of the application: 06/27/2010. Published: 04/20/2011.).

In this case, chondroitin sulfate is administered daily for 3-4 weeks on the 14th day after the start of standard basic therapy (after comparing and fixing the fragments).

According to the applicants, “The purpose of the drug on day 14 is due to the mechanism of cartilage mineralization, and it is at this time that the bones need glucosaminglycan chondroitin sulfate.” (End of quote)

However, as the studies revealed, bone marrow begins to form earlier than 14 days. Therefore, so late administration of the drug will not contribute to accelerating bone tissue regeneration. In addition, the daily (1 time per day) administration of the drug is not justified. The patient receives unnecessary inconvenience without improving the therapeutic effect.

The problem to which the invention is directed is the expansion of the arsenal of tools used, increasing the frequency of bone marrow formation and increasing the rate of bone callus formation by accelerating the appearance of fibrocartilage and cartilage callus and its mineralization.

The problem is solved due to the fact that in the method of treating injuries of the musculoskeletal system associated with a violation of the integrity of the bone, including the introduction of chondroitin sulfate intramuscularly, according to the invention, chondroitin sulfate is administered from 100 to 200 mg after 1 day, with the 1st injection chondroitin sulfate is administered as soon as possible from the moment of damage, mainly on the day of damage or the next day, preferably after fixation of the bone. A feature may be that with the first injection of chondroitin sulfate, 100 mg can be administered, and starting with the 3rd or 4th, 5th or 6th injection, 200 mg each. The general course of treatment can be at least 10-14 injections, and, as an object of treatment, along with other types of fractures, a closed radius fracture can be chosen.

To implement the method, a pharmaceutical preparation may be used, including chondroitin sulfate as an active component, characterized in that it is in the form of a ready-to-use solution or lyophilisate for the preparation of a solution for intramuscular administration, each of which contains 100 mg of chondroitin sulfate.

Another aspect of the invention is the use of chondroitin sulfate to accelerate the formation of fibrocartilage in the treatment of diseases of the musculoskeletal system associated with a violation of the integrity of the bone, for example, but not exclusively, with a closed fracture of the radial bone. In this case, the use of chondroitin sulfate is carried out by intramuscular injection with a dose of 100 to 200 mg after 1 day as soon as possible from the moment of injury, mainly on the day of injury or the next day, preferably after bone fixation, and the total course of use of chondroitin sulfate can be at least 10 injections before mineralization of fibrocartilage callus.

Chondroitin sulfates are polymeric sulfated glycosaminoglycans. They are specific components of cartilage. They are produced by the cartilage tissue of the joints, are part of the synovial fluid. A necessary building component of chondroitin sulfate is glucosamine, with a lack of glucosamine in the composition of the synovial fluid, a lack of chondroitin sulfate is formed, which affects the quality of the synovial fluid and can cause cracking in the joints.

Chondroitin sulfate has a tropism for cartilage, initiates the process of sulfur fixation in the synthesis of chondroitin-sulfuric acid, which, in turn, contributes to the deposition of calcium in the bones. It stimulates the synthesis of hyaluronic acid, strengthening the connective tissue structures: cartilage, tendons, ligaments, skin. It has analgesic and anti-inflammatory effects, is a chondroprotector, and promotes active regeneration of cartilage.

A feature of chondroitin among proteoglycans is its ability to retain water in the thickness of the cartilage in the form of water cavities that create good cushioning and absorb shock, which ultimately increases the strength of connective tissue. An important effect of chondroitin is its ability to inhibit the action of specific enzymes that destroy connective tissue, including lysosomal enzymes released as a result of the destruction of chondrocytes (elastase, peptidase, cathepsin, interleukin-1, etc.).

Natural consumption of chondroitin sulfate and other chondroprotective substances was carried out with the use of tendons, skin and cartilage of animals, especially fish. In connection with a decrease in the share of these products in the diet of modern humans (sometimes with a complete exception), as well as metabolic disorders, excessive functional loads and especially age-related decrease in the activity of synthetic processes, chondroitin sulfate must come in its finished form (or in the form of synthesis precursors) from the outside including food

Chondroitin sulfate slows down bone resorption and reduces Ca ²⁺ loss. Improves phosphorus-calcium metabolism in cartilage, accelerates the processes of its restoration, inhibits the degeneration of cartilage and connective tissue. It suppresses the activity of enzymes that cause damage to cartilage, stimulates the synthesis of glycosaminoglycans, promotes the regeneration of the articular bag and cartilage surfaces of joints, increases the production of intraarticular fluid. Reduces soreness and increases the mobility of affected joints. Possessing structural similarity with heparin, it can potentially prevent the formation of fibrin clots in the synovial and subchondral microvasculature.

From the above prior art it is known to use chondroitin sulfate as intramuscular injection for fractures. However, there is no information about the exact methods of using the drug with evidence from evidence-based studies, or the described methods do not significantly increase the frequency of bone marrow formation and shorten the start time for bone marrow formation.

Studying the feasibility of using chondroitin sulfate for fractures, it was unexpectedly found that the administration of the drug intramuscularly at 100 mg after 1 day with a subsequent increase in dose to 200 mg leads to a significant reduction in the duration of treatment. So in the treatment of closed radial bone fracture, the treatment period was 3-4 weeks. It was enough to carry out 10-14 injections.

The following are data from studies of the use of chondroitin sulfate in the treatment of radial fracture. But since the treatment processes are similar for different types of fractures, the application of the described treatment regimen extends to these types.

The study belonged to phase III: conducting a clinical study to establish the safety of the drug and its effectiveness for patients with a specific disease.

The study was open, i.e. both the patient and the research doctor knew what the patient was receiving - the studied drug or standard basic therapy (casting, prescribing analgesics, including paracetamol). Preparation for the introduction of the drug was carried out in a separate room of the clinical base - the treatment room.

The total duration of the study for the patient was no more than 28 ± 1 days, divided into 3 periods:

- screening period - 0-1 day

- treatment period - 28 ± 1 days (4 weeks)

the drug was prescribed 100 mg every other day intramuscularly for 5 days of the study, followed by an increase in the dose to 200 mg every other day intramuscularly, starting with the 4th injection (day 7 of the study). For the patients of the main group, the studied drug was administered in a hospital setting. In total, within the framework of this study, 14 injections of the study drug were provided;

on the 14th, 21st and 28th days, the x-ray of the radius (in two projections) was performed to determine the degree of formation of bone callus, a coagulogram;

- study completion period - 1 day

During the screening period V ₀ (day 0-1), the inclusion / non-inclusion criteria were evaluated and performed: a biochemical blood test, a clinical blood test, a general urine test, a coagulogram, an x-ray of the radius (in two projections), a collection of complaints and anamnesis, ECG (electrocardiogram), physical examination, measurement of blood pressure, heart rate, pregnancy test (for women of reproductive age), registration of concomitant therapy;

The treatment period will begin at visit V ₁ (day 1). After a final assessment of the inclusion / non-inclusion criteria based on the results of the tests, a decision was made to include the patient in the study, and 1: 1 randomization was carried out in one of two treatment groups: a solution of the drug Chondroitin sulfate was prescribed and administered (100 mg 1 injection every other day intramuscularly with a subsequent increase doses up to 200 mg every other day intramuscularly, starting with the 4th injection (day 7 of the study)) or standard basic therapy was prescribed (application of a plaster cast, administration of analgesics, including aratsetamola); conducted: physical examination, assessment of adverse events / serious adverse events, collecting complaints and medical history, registration of concomitant therapy;

On visits V ₂ (day 14) and V ₃ (day 21), radiography of the radial bone (in two projections), physical examination (including measurement of blood pressure and heart rate), complaints and anamnesis, coagulation, registration / correction (if necessary) of standard basic therapy, assessment of adverse events / serious adverse events, registration of concomitant therapy;

Study completion period — Visit V ₄ was scheduled for 28 ± 1 day of treatment, on an empty stomach. At this visit, a physical examination, ECG (electrocardiogram), clinical and laboratory examination, blood pressure measurement, heart rate, adverse event assessment, clinical analysis of blood and urine, biochemical analyzes, x-ray of the radial bone (in two projections), coagulogram, collection of complaints and history, registration of concomitant therapy, registration of standard basic therapy, (Fig. 1)

The studied population was represented by 200 patients of both sexes aged 18 to 75 years with an established and documented diagnosis of closed radial fracture, included in the study from several hospitals of the Russian Federation.

All patients who underwent screening were randomized to a group receiving therapy with the drug “Chondroitin sulfate solution” (100 people) and a group without therapy (comparison group) - standard basic therapy (100 people).

The dosage regimen and route of administration was selected on the basis of numerous studies: 1 injection (100 mg) every other day deeply in oil. It was planned to increase the dose of the test drug to 200 mg every other day intramuscularly, starting from the 4th injection (day 7 of the study) until the end of the study. Although, under certain conditions, an increase in dose can be made on the 3rd, 5th or 6th injection. Patients of the main treatment group came to the clinic in addition to administer the drug in a hospital setting (10 additional visits). In total, within the framework of this study, 14 injections of the study drug were performed. The dose increase may not occur depending on the tolerance of chondroitin sulfate by the patient.

Comparison of efficacy was carried out by testing the hypothesis of equality of the main research indicator (the frequency of bone marrow formation according to x-ray data) in the therapeutic research groups (Group 1: therapy with the drug “Chondroitin sulfate solution”, Group 2: standard basic therapy).

Performance Options

- The rate of formation of bone callus (according to x-ray studies)

- The frequency of bone marrow formation (according to x-ray examination)

X-ray studies were carried out in each patient at the time of the screening visit (day 0 of the present study), as well as at Visits 2-4 (day 14, day 21 and day 28 of the present study). During X-ray studies at these visits, the following parameters of bone callus formation were evaluated (the stage of formation of angiogenic bone structures and mineralization of the protein base of the regenerate):

- formation of fibrocartilaginous callus (nominal indicator with possible categories “yes” / “no”);

- mineralization of fibrocartilaginous corn (nominal indicator with possible categories “yes” / “no”);

- X-ray visualization of the fracture line (nominal indicator with possible categories “yes” / “no”)

For these x-ray indicators of bone marrow formation, the fixation time of the indicator was recorded (day 14, day 21 or day 28), thus, the indicators of the rate of bone marrow formation will be obtained:

- the rate of formation of fibrocartilage bone callus (ordinal indicator with the possible categories of “day 14”, “day 21”, “day 28”);

- the rate of mineralization of fibrocartilage callus (ordinal indicator with the possible categories of “day 14”, “day 21”, “day 28”);

- time to the disappearance of the visually marked fracture line (ordinal indicator with the possible categories of “day 14”, “day 21”, “day 28”).

The main criterion for the effectiveness of therapy was the assessment of the frequency of bone marrow formation. The analysis was carried out by evaluating radiographs at all visits at a nominal rate, assessed as “yes”, “no”. Three indicators were considered: the frequency of formation of fibrocartilage callus, the frequency of bone marrow mineralization (the beginning of the callus mineralization was considered as a positive response) and the frequency of x-ray visualization of the fracture line.

An additional criterion for effectiveness was an indicator of the rate of formation of bone marrow, which was calculated in days by evaluating radiographs by a nominal indicator, assessed as “yes”, “no”. Three indicators were considered: the rate of formation of fibrocartilage of the callus, the mineralization rate of fibrocartilage of the callus, and the time until the disappearance of the visually marked fracture line.

A statistical analysis was performed to evaluate the effectiveness, including descriptive statistics for groups, analysis using the Cochren Q test for dependent samples (intragroup analysis) and a comparative analysis of the control and study groups using the Mann-Whitney criterion (intergroup analysis).

The results of these calculations are presented in tables 1-3.

As shown in table 1.1, at visit 1, none of the patients in the study group had fibrocartilage callus, at visit 2 it was formed in 92% of patients, by visit 3 this percentage was 95%, and by visit 4 it was 100%. The rate of corn formation in 92% was 14 days, in 3% - 21 days and in 5% - 28 days.

As shown in table 1.2, at visit 1, none of the patients in the control group developed fibrocartilage callus, at visit 2 it was formed in 69% of patients, by visit 3 this percentage was 90%, and by visit 4 it was 100%.

The rate of corn formation in 69% of patients was 14 days, in 21% - 21 days and in 10% - 28 days.

As shown in table 1.3, the difference between visits 3 and 2 in terms of the frequency of formation of fibrocartilage in the study group was 3%, and between visits 4 and 3 - 5%.

Table 1.4. Estimation of the frequency of fibrocartilage callus formation in the control group (Cohren nonparametric test)

As shown in table 1.4, the difference between visits 3 and 2 in terms of the frequency of formation of fibrocartilage in the control group was 21%, and between visits 4 and 3 - 10%. (Fig. 2)

As shown in table 1.5. at visit 2 and visit 3, statistically significant differences were revealed (at p = 0.005) between the studied control group in terms of the frequency and rate of formation of fibrocartilage. (Fig. 3)

As shown in table 2.1. at visit 1 and 2, none of the patients in the study group showed mineralization of fibrocartilaginous callus, by visit 3 this process began in 68% of patients, and by visit 4 - 94%.

The time of onset of mineralization of fibrocartilaginous callus (mineralization rate) in the study group in 68% was 21 days and in 26% - 28 days.

As shown in table 2.2. at visit 1 and 2, none of the patients in the control group showed mineralization of fibrocartilage callus, by visit 3 this started in 61% of patients, and by visit 4 - in 85%.

The time of onset of mineralization of fibrocartilaginous callus (mineralization rate) in the control group was 61 days - 21 days and 24% - 28 days.

As shown in table 2.3. the difference between visits 4 and 3 in terms of the frequency of onset of mineralization of fibrocartilage in the study group was 26% (Fig. 4).

As shown in table 2.4. the difference between visits 4 and 3 in terms of the onset frequency and mineralization rate of fibrocartilage in the control group was 24%. (fig. 5)

As shown in table 2.5. significant differences were found (p = 0.003) between the study and control groups in terms of the frequency and mineralization rate of fibrocartilage of the cornea (Fig. 6).

In all patients of the study group, the fracture line was visualized until the end of the study.

In all patients of the control group, the fracture line was visualized until the end of the study.

There are no statistically significant differences between the value registered at 1 visit and the values established at subsequent 2, 3 and 4 visits

There are no statistically significant differences between the value recorded at 1 visit and the values established at subsequent 2, 3 and 4 visits.

By the frequency of X-ray visualization of the fracture line and the rate of disappearance of the fracture line, no significant differences were found when comparing the patients of the study and control groups.

Based on the data presented, the following conclusions are made:

1. In terms of the frequency of formation of fibrocartilage callus at visit 1, none of the patients in the study and control groups did not form this structure, at visit 2 it was formed in 92% of patients in the study group, by visit 3 this percentage was 95%, and to visit 4 - 100%. In the control group, this indicator amounted to 69% to visit 2, to visit 3 - 90%, and to visit 4 - 100%. The difference between visits 3 and 2 in terms of the frequency of formation of fibrocartilage in the study group was 3% (in the control group - 21%), and between visits 4 and 3 - 5% (in the control group - 10%).

2. The rate of callus formation in the study group in 92% of patients was 14 days, in 3% - 21 days and in 5% - 28 days. In the control group, this indicator was equal in 69% of patients - 14 days, in 21% - 21 days and in 10% - 28 days.

3. There were revealed statistically significant differences between the studied and control groups (at p = 0.005) in terms of the frequency and rate of formation of fibrocartilaginous callus.

4. At visit 1 and 2, all patients in both mineralization groups did not have fibrocartilage callus; by visit 3, this process began in 68% of patients, and by visit 4, in 94%. In the control group, the onset of mineralization was observed in 61% of patients at visit 3; by visit 4, this percentage was 85%. The difference between visits 4 and 3 in terms of the frequency of onset of mineralization of fibrocartilage in the study group was 26%, and in the control group - 24%.

5. The time of onset of mineralization (mineralization rate) of fibrocartilaginous callus in the study group in 68% was 21 days and in 26% - 28 days (in the control group in 68% - 21 days and in 21% - 28 days).

6. Statistically significant differences were established (at p = 0.003) between the study and control groups in terms of the frequency and mineralization rate of fibrocartilage of corns on the fourth visit.

7. In all patients in the study and control group, a visually observed fracture line was observed at all visits until the end of the study.

Thus, the analysis carried out may indicate the effectiveness of the drug chondroitin sulfate in the treatment of patients with closed fractures of both the radius and other types of fractures according to the proposed method.

The preparation used in accordance with the invention may be in the form of a ready-to-use solution or lyophilisate for the preparation of a solution for intramuscular administration, each of which contains 100 mg of chondroitin sulfate.

An important condition is the earliest possible appointment of the course of administration of chondroitin sulfate - as soon as possible from the moment of damage. The most optimal is to ensure the introduction of the drug immediately on the day of injury or the next day. However, if this is impossible (at the moment there is no drug, the patient is outside the fast reach of medical institutions, etc.), the administration of chondroitin sulfate can be started any of the following days (3rd, 4th, 5th etc.). Naturally, it should be understood that the later the introduction of the drug begins, the later the formation of fibrocartilage callus and its subsequent mineralization will begin.

Depending on the type and complexity of the fracture, the course of treatment with chondroitin sulfate can be increased to 25-30 injections.

Also, depending on the patient's tolerance of chondroitin sulfate, an increase in dose to 200 mg may not be performed. In this case, the entire course is carried out with a dosage of 100 mg.

The optimal scheme is when the dose increase occurs on the 4th injection (the 7th day of the course - the end of the first week). Although, under certain conditions, an increase in dose can be made on the 3rd, 5th or 6th injection. It is possible that under certain conditions the entire course can be carried out at a dosage of 200 mg.

The introduction of chondroitin sulfate from the first day promotes earlier activation of cartilage cells. This, in turn, makes it possible to accelerate the formation of fibrocartilaginous callus and provide earlier dates for its mineralization. Which ultimately contributes to a more rapid formation of bone marrow during fractures and cracks.

Claims (3)

1. A method of treating injuries of the musculoskeletal system associated with a violation of the integrity of the bone, by stimulating the formation of bone marrow, including the injection of chondroitin sulfate intramuscularly, characterized in that chondroitin sulfate is administered in a dose of 100 to 200 mg after 1 day, with a general course of 10 -14 injections, while the first injection of chondroitin sulfate is carried out as soon as possible from the moment of damage, mainly on the day of damage or the next day, moreover, from the first injection of chondroitin with lfat administered at 100 mg, and from the 3rd or 4th, or 5th or 6th injections administered chondroitin sulfate 200 mg. 2. The method according to p. 1 characterized in that as a damage to the musculoskeletal system associated with a violation of the integrity of the bone, choose a closed fracture of the radius. 3. The use of chondroitin sulfate in an amount of 10-14 injections of 100-200 mg to accelerate the formation of bone marrow in the treatment of injuries of the musculoskeletal system associated with impaired bone integrity.

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